Research in context
Evidence before this study
We searched PubMed for phase 3 clinical trials on advanced urothelial carcinoma published in English between Jan 1, 2005, and Jan 1, 2014, using the MeSH search terms “advanced” AND “bladder cancer”, “urothelial carcinoma”, “transitional cell carcinoma”. We identified 17 articles. We examined the articles specific to treatment of patients in the first-line setting, along with international congress presentations during the time period. We identified an unmet clinical need for effective and tolerable approaches to the treatment of patients with baseline characteristics that rendered them ineligible for cisplatin-based chemotherapy. No such treatments seemed to exist or be approved by the US Food and Drug Administration, European Medicines Agency, or related agencies, and the cytotoxic drugs commonly used in this population were consistently associated with toxicity and poor overall survival despite treatment.
Added value of this study
In this study, the humanised monoclonal anti-programmed death-ligand 1 antibody atezolizumab was assessed in patients with previously untreated, locally advanced or metastatic urothelial cancer who were ineligible for cisplatin-based chemotherapy. The original trial design for this study was focused on patients with disease progression during or after platinum-based chemotherapy and an exploratory cohort of first-line cisplatin-ineligible patients; however, in view of the potential for benefit in the first-line setting, the exploratory cohort was expanded to about 100 patients, using similar statistical assumptions. Objective responses by independent assessment according to Response Evaluation Criteria In Solid Tumors version 1.1 were durable, with 70% of patients continuing to respond after a median follow-up duration of almost 1·5 years. Overall survival also seemed to surpass historical rates, although differences in patient populations between studies, among other factors, complicate comparison. Atezolizumab also generally seemed to be safe and well tolerated in a patient population heavily dominated by renal insufficiency. Exploratory analyses to improve the understanding of the immune biology of atezolizumab efficacy identified correlates of response and survival including The Cancer Genome Atlas subtype and mutation load, which warrant further study as potential biomarkers for this drug in metastatic urothelial cancer.
Implications of all the available evidence
Cisplatin-based chemotherapy is the preferred first-line treatment for metastatic urothelial cancer and the only treatment shown to improve survival in patients with previously untreated disease. However, only a minority of patients with metastatic urothelial cancer receive first-line treatment with cisplatin-based chemotherapy. The population of patients who are ineligible for cisplatin has been under-represented in clinical studies in the past 30 years and as a result, these patients have poor outcomes. Atezolizumab shows potential as a first-line treatment option for these patients. Furthermore, biomarker data validate reports of this drug in the platinum-treated setting that linked intrinsic The Cancer Genome Atlas subtypes and mutation load with immunotherapy response.